1. Field of the Invention
The present invention relates to a novel process for producing an optically active N-protected-N-methyl-phenylalanine derivative; more specifically, the invention relates to a novel process for producing an optically active N-protected-N-methyl-4-halogenophenylalanine purified chemically and optically to a high purity. The derivative is important as an intermediate for the production of pharmaceutical agents; and in accordance with the invention, the derivative at such a high purity chemically and optically that the derivative can sufficiently be used as the intermediate for the production of pharmaceutical agents can be produced very efficiently and industrially.
2. Description of the Background
Optically active N-protected-N-methyl-4-halogenophenylalanine, for example N-tert-butyloxycarbonyl-N-methyl-L-4-chlorophenylalanine, is known to be useful as an intermediate for the production of pharmaceutical agents (see PCT Japanese Patent Kohyou Publication No. JP-A-10-509151).
So as to use the phenylalanine derivative as an intermediate for the production of pharmaceutical agents, it is required to industrially produce the compound purified chemically and optically to a high purity.
According to the findings of the present inventors, optically active N-protected-N-methyl-4-halogenophenylalanine can be produced by subjecting optically active N-protected-4-halogenophenylalanine, for example N-tert-butyloxycarbonyl-L-4-chlorophenylalanine to N-methylation step but contains the optical isomer thereof as a part of impurities therein. However, it is difficult to remove the optical isomer as an impurity contained in the derivative thus prepared, even by subjecting the derivative to crystallization step, so the intended optical purity cannot readily be yielded. Thus, it is difficult to produce the derivative at a high purity chemically and optically, and at a high yield by such a method. The repetition of the crystallization step makes the production process laborious and involves the reduction of the yield, which is not preferable industrially. Therefore, it is needed to develop a process for industrially and efficiently producing an optically active N-protected-N-methyl-4-halogenophenylalanine, chemically and optically purified to a high purity.
It is a purpose of the present invention to develop a process for industrially and efficiently producing the optically active form purified to such a high purity that the optically active form can sufficiently be used as an intermediate for the production of pharmaceutical agents.
So as to solve the problem, the present inventors have made investigations with efforts and have found that when a salt is recovered (deposited) by subjecting an optically active N-protected-N-methyl-4-halogenophenylalanine at least containing the optical isomer thereof as an impurity to a step of salt formation and is then isolated, the optical isomer and the like as impurities contained therein are nearly removed from the resulting salt and that an optically active N-protected-N-methyl-4-halogenophenylalanine purified to a high purity can be recovered at a high yield by subjecting the salt thereby recovered to desalting. Thus, the present invention has been achieved.
The isolation of the optical isomer as an impurity is not readily done by the crystallization procedure of the free form, but through the process of salt formation, the impurity can be removed very efficiently. Hence, the intended compound at a highly chemical and a highly optical purity can be recovered at a high yield, taking the subsequent crystallization procedure of the free form into consideration.
In other words, the present invention relates to a process for producing an optically active N-protected-N-methyl-4-halogenophenylalanine at a high purity (including a free form thereof and/or a salt form thereof), comprising the steps of: subjecting an optically active N-protected-N-methyl-4-halogenophenylalanine containing at least the optical isomer thereof as an impurity to a process of salt formation to deposit (precipitate) it and isolating the salt of the optically active form. The production of an optically active form, which may be in the free form or in the salt form such as dicyclohexylamine salt) of the intended compound, at least by way of the separation or isolation step in the form of salt in such manner, is encompassed with the scope of the present invention.
Additionally, the ultimate purpose in accordance with the present invention is the acquisition (recovery) of the optically active form purified to a high purity at a high yield, which is useful as an intermediate for the production of pharmaceutical agents.
Meanwhile, the DCHA salt of an optically active N-protected-N-methyl-phenylalanine with no substituent at 4-position of the phenyl group has already been known (see Memoirs of the Faculty of Science, Kyushu University Ser. C, Vol. 9, No. 1, 1974, 131-138). According to the reference, however, the free form of the N-protected-N-methyl-phenylalanine is in the form of oily matter and has therefore physical properties different from those of the subject compound of the present invention, of which the free form is recovered in a solid state. According to the reference, additionally, the compound is first prepared as DCHA salt and is then isolated in a solid state, but the reference never includes any description suggesting the purification effect as described in the present invention. Further, the problem to be solved by the present invention, namely final efficient acquisition (recovery) of the free form at a high purity, is never present in the reference.
The substance to be purified in accordance with the present invention is an optically active N-protected-N-methyl-4-halogenophenylalanine containing at least the optical isomer thereof as an impurity. A halogen atom, preferably chlorine atom or bromine atom, is present at 4-position of the phenyl group composing the phenylalanine derivative.
The purpose lies in the production of the optically active form as an intermediate for the production of pharmaceutical agents and the optically active form then may satisfactorily be any of the L and D forms. For producing the L form at a high purity as the intended compound, the optical isomer as an impurity corresponds to the D form of the intended compound; for producing the D form, the impurity corresponds to the L form.
Such impurity in the form of isomer contained in the substance to be purified in accordance with the present invention generally contaminates the substance through side reactions in the course of the production for the intended compound. From the respect of purification efficiency, the content of the isomer as an impurity is preferably about 1 to 10% by weight, more preferably about 1 to 5% by weight, and still more preferably about 1 to 3% by weight. By the process of the present invention, a purified product (in the form of salt or in the free form) can be obtained at an optical purity of 99.0% ee or more, optically preferably.
The amino group of the above-mentioned phenylalanine derivative as the intended compound in accordance with the present invention has a protective group; and as the protective group, protective groups for general use for amino group are illustrated, such as tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Z), and 9-fluorenylmethyloxycarbonyl group (Fmoc).
The optically active N-protected-N-methyl-4-halogenophenylalanine of the present invention can be produced by the N-protection and N-methylation of 4-halogenophenylalanine (optically active form).
For carrying out the N-protection and N-methylation of 4-halogenophenylalanine (optically active form), the protective method for the amino group of amino acid and general methods known as N-methylation method can be adopted. For the N-methylation, a method comprising the reaction of sodium hydride with methyl iodide is general. For the production in practice, satisfactorily, the N-protection (with Boc and the like) is first effected, followed by the N-methylation. It is needless to say that an optically active form at a high optical purity is preferably used as the 4-halogenophenylalanine (optically active form), but even in that case, optical isomer impurities are generated by side reactions and contaminate the resulting product through the steps of the N-protection and N-methylation.
For producing an optically active 4-halogenophenylalanine, herein, an already known method is utilized, whereby the optically active 4-halogenophenylalanine can readily be produced. For example, a method comprising introducing an intended halogen atom at 4-position of the phenyl group in an optically active phenylalanine [see J. Med. Chem., 17(5), 556 (1974)] can be listed.
Additionally, a synthesis method by way of aminomalonic acid derivative [see Tetrahedron: Asymmetry, 9, 3274 (1998)] is also used. More specifically, 2-acylamino-2-(4-halogenobenzyl)-malonate diester, preferably 2-acetylamino-2-(4-halogenobenzyl)-malonate diester (diethyl ester and the like) is hydrolyzed with alkali and the like, to prepare N-acyl (acetyl and the like)-DL-halogenophenylalanine, which is then allowed to react with acylase, to obtain (recover) the intended (desired) optically active form at a high purity. Herein, the raw material of 2-acylamino-2-(4-halogenobenzyl)malonate diester can readily be produced by allowing 2-acylaminomalonate diester and 4-halogenobenzyl halide to react together.
In accordance with the present invention, the intended optically active form as the principal component is preferentially deposited in the form of salt and then isolated during the process of salt formation of the substance to be purified, whereby impurities such as optical isomer can be removed into solvent. The base for composing the salt includes amines such as dicyclohexylamine (DCHA) and cyclohexylamine. The DCHA salt is particularly preferable because the DCHA salt is excellent in terms of purification effect.
For the recovery in the form of salt, first, an amine such as DCHA or the like is added to a solvent dissolving therein an optically active N-protected-N-methyl-4-halogenophenylalanine and impurities such as the optical isomer thereof, to precipitate (deposit) the optically active N-protected-N-methyl-4-halogenophenylalanine in the form of salt, which is then isolated, satisfactorily. As the solvent, ethyl acetate, isopropyl acetate, acetone, ethanol, isopropanol and a mixture solvent thereof are listed. Because the crystallinity of the resulting amine salt is excellent, ethyl acetate is particularly preferable. The formation of the salt is effected at a temperature of about 10 to 50xc2x0 C. in the case that ethyl acetate for example is used as the solvent. Generally, impurities can be removed to a level such that the resulting purified product can sufficiently be used as an intermediate for the production of pharmaceutical agents, by carrying out once such process of salt formation and isolation. In accordance with the present invention, accordingly, the intended compound at a high purity can be obtained at a high yield. Such process of salt formation and isolation can satisfactorily be repeated, but in that case, the yield is reduced. Thus, generally, the repetition is not needed.
For purifying the free form itself by crystallization procedure, not by way of salt form, the purification efficiency is significantly reduced; when it is intended to raise the purity, the yield is significantly reduced.
So as to recover the free form from the thus prepared salt of an optically active N-protected-N-methyl-4-halogenophenylalanine, a generally known method can be used for the conversion to free carboxyl group. Using aqueous solutions prepared by dissolving an acid, for example sulfuric acid and aqueous potassium hydrogen sulfate solution, an extraction procedure is effected for the desalting.
For the recovery of the intended optically active N-protected-N-methyl-4-halogenophenylalanine in the form of salt, generally, a product at a high purity can be recovered, in which impurities have been removed sufficiently, by effecting the process of salt formation and isolation as described above. For the recovery thereof in the free form, the resulting salt thus prepared (in which impurities have been removed sufficiently at the process of salt formation and isolation) is desalted, from which the solvent dissolving the free form therein is then distilled off, whereby an optically active N-protected-N-methyl-4-halogenophenylalanine in a solid form at a high purity can readily be recovered and obtained. However, the crystallization procedure for the recovery thereof in the crystalline form is rather simple and conventional for industrial production, from the standpoint of the recovery of the intended compound, and furthermore, an additional purification effect can be expected as well, preferably.
For the practice of the crystallization, a known crystallization procedure can be utilized. A solution dissolving therein the intended compound is subjected to crystallization by an appropriate combination of general crystallization means such as cooling in atmosphere, concentration, cooling, addition of seed crystal, standing, and agitation (stirring). Specifically, a poor solvent such as heptane, hexane, toluene, xylene, methyl-tert-butyl ether, etc. is added to the free form at a state dissolved in a solvent, for example ethyl acetate, isopropyl acetate, acetone, ethanol, isopropanol, etc., whereby the free form can readily be crystallized and isolated, to obtain the intended compound.
As apparently shown in the descriptions insofar and the descriptions of examples below, an optically active N-protected-N-methyl-4-halogenophenylalanine (including the free form and/or the salt form thereof) purified to a high purity can be produced at a high yield according to the process in the present invention.